In the operation of biorefineries, performing a quantitative, economic, and environmental assessment of process equipment design without the use of related software, is time-consuming, difficult, and sometimes impossible due to the complexity and high volume of calculations. The wrong choice of software in simulation and modeling can cause a lot of damages and lead to inaccurate results. Therefore, choosing an integrated system and specialized software can be the most important tool to achieve the planned goals. This study is aimed to investigate how and when to make the right software choice to enhance the performance and profits and diminish the risks, operating costs, and environmental impacts. The software used in the stages of cultivation, harvesting, conversion of microalgae, process optimization, and environmental impact assessment of biorefineries are introduced in various sections of this study, and the advantages and disadvantages of each of them are given along with some practical examples. The software tools investigated in this study include Aspen plus, SuperPro Designer, BioSTEAM, IPSEpro, WinGEMS, Unisim Design, Virtual Sugarcane Biorefinery (VSB) modeling software, Simapro, OpenLCA, and, etc., which can be used according to feed and process conditions and products. To our knowledge, we did not encounter any similar reviews or reports, and this review is the first of its kind on this topic. Display omitted •Software tools for microalgae biorefineries were presented.•Biofuel production modeling and optimization was investigated.•How and when to choose the right software was developed.•Reduction of the risks, operating costs, and environmental impacts by software was introduced.